Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].[CH:25](=O)[C:26]([CH3:29])([CH3:28])[CH3:27].N1CCCC1>C(#N)C>[C:26]([CH:29]1[O:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:9]=[C:4]2[C:1](=[O:3])[CH2:2]1)([CH3:28])([CH3:27])[CH3:25]
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: CC(C)(C)C=O
Solvent: C1CCNC1
Solvent: CC#N
Product: CC(C)(C)C1CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1
Temperature: 70 °C

Procedure:
To the product of Example 4 Step A (0.75 g, 2.09 mmol) was added pivalaldehyde (2. mL, 20.9 mmol), pyrrolidine (0.26 mL, 3.14 mmol) and acetonitrile (15 mL). The reaction was heated to 70° C. for 19 h. The reaction was then concentrated and the residue was purified directly by flash chromatography on silica gel gradient eluted with 0-35% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 426.3 (M+1), 428.3 (M+3); Rt=4.32 min.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1.C(O)(=O)C.O.[Zn]>[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([OH:31])=[O:4])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)c1ccccc1C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10452.2 %

Procedure:
--2,2,2-Trichloroethyl-2-[(z,z,z) octadeca-6,9,12-trienoyl]benzoate (15 1 g) was dissolved in a mixture of tetrahydrofuran (750 ml), acetic acid (675 ml) and water (75 ml). Zinc dust (150 g) was added. The mixture was stirred at room temperature under nitrogen for 1.5 hours and then allowed to stand for twenty hours. Excess zinc and zinc salts were filtered off through Celite washing the filter pad with tetrahydrofuran (100 ml) and the flitrate was evaporated at 25° C./10 mmHg to remove the tetrahydrofuran. The acetic acid and water was then removed at 25° C./0.5 mmHg. Higher temperatures tend to decompose the product. The resulting oil was dissolved in diethyl ether (1000 ml) and the resulting solution was washed with water (4×200 ml). After drying (Na2SO4), the ether was evaporated (25° C./10 mmHg) to give a pale yellow oil which was subjected to a dry column (Packing: Matrex silica (1 Kg), pore size 60A, particle size 35-70μm, Fraction size: 1000 ml). The requisite tractions were collected, the solvent evaporated as before, the last traces being removed at 25° C./0.1 mmHg to give 2-[(z,z,z) octadeca-6,9,12,-trienoyl]benzoic acid, (77.8 g, 68%) as a pale orange oil which solidified to a wax in the refrigerator.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:32])[S:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[ClH:1].[ClH:1].[ClH:1].[CH:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([C:26]3[CH:25]=[CH:24][C:23]([S:20]([N:19]([CH3:32])[CH3:18])(=[O:21])=[O:22])=[CH:28][CH:27]=3)=[N:7][CH:6]=2)[CH2:10][CH2:11]1)([CH3:17])[CH3:16]
Reactant: CC(C)N1CCN(Cc2ccc(Cl)nc2)CC1
Reactant: CN(C)S(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)N1CCN(Cc2ccc(-c3ccc(S(=O)(=O)N(C)C)cc3)nc2)CC1
Product: Cl

Procedure:
1-(6-Chloropyridin-3-ylmethyl)-4-isopropylpiperazine (0.5 g, 1.97 mmol) and 4-(N,N-dimethylaminosulfonyl)phenylboronic acid (0.496 g, 2.2 mmol)) were mixed with catalyst and reacted in the same manner as in example 18. The title compound was isolated as white crystals of the trihydrochloride. Yield: 660 g (71%)
Reaction SMILES: O=[C:2](O)[C@@H:3]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]1[OH:5].[NH2:13][C:14]1[C:19]([NH2:20])=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=1>>[C@@H:3]1([C:2]2[NH:20][C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:21])[N:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]1[OH:5]
Reactant: O=C(O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1ncnc(N)c1N
Product: Nc1ncnc2nc([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[nH]c12

Procedure:
Hydrolysis of this product yielded 2,5-anhydroallonic acid and reaction of this acid with 4,5,6-triamino pyrimidine, after cyclization, yielded the nucleoside, 8-β-D-ribofuranosyl adenine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH:14][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(CN)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(CNCc1ccc(F)cc1)OC
Reaction time: 8 h
Yield: 93.9 %

Procedure:
12.4 g of 4-fluorobenzaldehyde were dissolved in 100 mL of toluene and reacted with 10.5 g of 2-aminoacetaldehyde dimethylacetal and 1.90 of p-toluenesulfonic acid monohydrate for two hours at a Dean Stark apparatus. The solution was allowed to cool down, extracted with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated to dryness. The crude product was dissolved in 100 mL of ethanol. 1.89 g of sodium borohydride were added portionwise. Stirring was continued overnight. For workup, acetic acid was added until no gas evolution could be observed. Then the solution was evaporated to dryness, taken up in dichloromethane and washed twice with water. The organic layer was extracted with brine, dried over magnesium sulfate and evaporated to dryness. The obtained crude product (20 g) was used for further reactions without purification. Rt=0.86 min (Method B). Detected mass: 182.1 (M-OMe−), 214.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:16]=[C:15]([CH3:17])[NH:14][C:8]=3[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]2=[N:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([N:14]1[C:8]2[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[C:7]=2[CH:16]=[C:15]1[CH3:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc2c(cc([N+](=O)[O-])c3nnc(C)n32)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc([N+](=O)[O-])c3nnc(C)n32)n1Cc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 1,7-dimethyl-4-nitro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.30 g, 1.3 mmol, from Step 1) in N,N-dimethylformamide (5 mL) was added Cs2CO3 (0.51 g, 1.6 mmol). After stirring for 1 hour, benzyl bromide (0.18 mL, 1.6 mmol, Aldrich) was added, and the reaction mixture was stirred overnight, after which time water was added, and the reaction mixture was stirred for 5 minutes. Ethyl acetate was added, and the mixture was stirred overnight. The product, which had precipitated, was isolated by filtration. The product was washed sequentially with ethyl acetate, water, and again with ethyl acetate. Yield: (0.20 g, 48%). LCMS (M+H)+: 322.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]#[C:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1>C1COCC1.[Pd]>[F:19][CH:2]([F:1])[CH2:3][CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#CC(F)F)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CCC(F)F)CC1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-(3,3-difluoroprop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylate (350 mg, 1.273 mmol) in 30 mL of anhydrous THF was stirred with Pd/C (200 mg) under H2 atmosphere at 15 psi at 48° C. for 8 h. The reaction mixture was cooled to r.t. and filtered, and the resulting mixture was concentrated in vacuo to afforde 293 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 5.89 (tt, J=56.9, 4.3 Hz, 1H), 3.84 (dd, J=9.8, 3.5 Hz, 2H), 3.24-3.10 (m, 2H), 2.05-1.89 (m, 2H), 1.67-1.60 (m, 2H), 1.55 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([C:17]2[NH:18][C:19]3[C:24]([C:25]=2[NH:26][C:27](=[O:30])[CH2:28][CH3:29])=[CH:23][CH:22]=[C:21]([Cl:31])[CH:20]=3)=[O:16])[CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(=O)(O)[O-].[Na+]>[ClH:31].[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([C:17]2[NH:18][C:19]3[C:24]([C:25]=2[NH:26][C:27](=[O:30])[CH2:28][CH3:29])=[CH:23][CH:22]=[C:21]([Cl:31])[CH:20]=3)=[O:16])[CH:10]=1
Reactant: CCC(=O)Nc1c(C(=O)c2cc(NC(=O)OC(C)(C)C)ccn2)[nH]c2cc(Cl)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)Nc1c(C(=O)c2cc(N)ccn2)[nH]c2cc(Cl)ccc12
Product: Cl

Procedure:
2-[4-(tert-Butoxycarbonyl)aminopyridine-2-carbonyl]-6-chloro-3-(propionylamino)indole (step 4, 118 mg, 0.266 mmol) was treated with trifluoroacetic acid (4 ml) at room temperature for 1 h. The mixture was concentrated and azeotroped with toluene to give an oily residue. The residue was basified with saturated aqueous sodium bicarbonate (30 ml) and extracted with dichloromethane (30 ml×3). The organic phase was dried (K2CO3), and concentrated to afford the free base of title compound. The free base was dissolved in 10% HCl—MeOH (4 ml) and then evaporated. The residue obtained was crystallized from ethanol-diethyl ether to give the title compound. m.p.: 199-204° C. (decomposition) 1H-NMR (DMSO-d6) δ: 12.03 (1 H, br s), 10.41 (1 H, br s), 8.17 (1 H, d, J=7.3 Hz), 7.93 (1 H, d, J=8.9 Hz), 7.48 (1 H, d, J=1.6 Hz), 7.18 (1 H, dd, J=1.6, 8.7 Hz), 7.12 (1 H, d, J=1.8 Hz), 6.88 (1H, dd, J=7.4, 2.0 Hz), 2.18 (1 H, q, J=7.4 Hz), 0.82 (3 H, t, J=7.4 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25](Br)=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd]Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:25]2[CH:24]=[C:23]3[C:28]([CH2:29][CH2:30][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22]3)=[CH:27][CH:26]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc2C1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C1
Yield: 92.7 %

Procedure:
A mixture 4-(trifluoromethyl)phenylboronic acid (987 mgs, 5.2 mmol), 7-Bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.2 g, 4.0 mmol), potassium carbonate (1.1 g, 8.0 mmol), PdCl2 (dppf) (146 mgs, 0.2 mmol) in toluene/ethanol/water (3 mL/1.5 mL/1.5 mL) was heated in pressure vessel at 120° C. for 2 h. The mixture was then concentrated and chromatographed (40 grams of SiO2, 30% EtOAc/hexanes) to provide the title compound (1.4 g, 92% yield over two steps).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[N+]([C:25]1C=CC(S(OC)(=O)=O)=CC=1)([O-])=O.O>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[N:8]([CH3:25])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c(-c2cccc(Cl)c2)cc2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(Cl)c2)cc2ccc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
7-Bromo-3-(3-chlorophenyl)isoquinolin-1(2H)-one (Intermediate 23A) (0.1 g, 0.299 mmol) was dissolved in THF (4 mL), under an atmosphere of nitrogen. Sodium hydride (0.018 g, 0.448 mmol) was added and reaction stirred for 30 minutes. The reaction was then cooled using an ice bath and methyl 4-nitrobenzenesulfonate (0.065 g, 0.299 mmol) was added. The reaction was allowed to warm to room temperature and left to stir overnight. Water was added to the reaction mixture and extracted with EtOAC (×2). The organics were combined and washed with brine, dried (MgSO4) filtered and concentrated under reduced pressure. The mixture was purified on silica (25 g column on Isolera 4) eluting with 0-10% methanol in dichloromethane to afford 7-bromo-3-(3-chlorophenyl)-2-methylisoquinolin-1(2H)-one (51 mg, 0.15 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]=[O:12].N1C2C(=CC=CC=2)C=[C:14]1C(OCC)=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:14])[CH:8]=[C:7]2[CH:11]=[O:12]
Reactant: O=Cc1c[nH]c2c(F)cccc12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: Cn1cc(C=O)c2cccc(F)c21
Yield: 43 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 7-fluoro-1H-indole-3-carboxaldehyde (0.5 g, 3.1 mmole) for the ethyl indole-2-carboxylate, the title compound (0.23 g, 43%)was prepared as a viscous oil: MS (ES) m/e 178 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][CH2:25][CH3:26]>CN1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][CH3:26]
Reactant: CCCI
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: CCCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 43.3 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 153 mg, 0.5 mmol) and iodopropane (0.25 mL, 2.54 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube overnight. The reaction mixture was purified by preparative HPLC to give a brown gum which was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium thiosulfate (three times) and brine, dried (sodium sulfate), filtered, evaporated, and dried under high vacuum to give (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-propyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (75 mg, 39%) as a beige foam. ES(+)-MS (M+H) 347.
Reaction SMILES: [BH4-].[Na+].[ClH:3].[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[N:15]=[C:16]([C:33](=[O:35])[CH3:34])[CH:17]=[C:18]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[C:19]=12.O>CO>[ClH:3].[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[N:15]=[C:16]([CH:33]([OH:35])[CH3:34])[CH:17]=[C:18]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[C:19]=12
Reactant: CC(=O)c1cc2c(C)c(C)n(Cc3cccc(F)c3)c2c(N2CCc3ccccc3C2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(C)n(Cc2cccc(F)c2)c2c(N3CCc4ccccc4C3)nc(C(C)O)cc12
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
Sodium borohydride (5.3 mg, 0.14 mmol) was added at 0° C. to a solution of 1-[7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-yl]-ethanone hydrochloride (20 mg, 0.05 mmol) prepared in Example 855 in anhydrous methanol (2 ml). The reaction mixture was stirred for 10 minutes at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v). The resulting residue was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 7.1 mg of the titled compound as a white solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:32][C:22]1[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[NH:25][C:21]=1[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:6])=[O:5])=[CH:12][CH:11]=1)[CH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1)C1CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2[nH]c(-c3ccccn3)cc2Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in tetrahydrofuran (5 mL) was added N-chlorosuccinimide (61.2 mg) at 0° C., and the mixture was stirred overnight at room temperature, and further at 50° C. for 1 day. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (49.0 mg, yield 23%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 471 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:17]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1)(=[O:19])[CH3:18]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:29]2[CH:28]=[CH:27][C:24]3[CH2:25][CH2:26][N:20]([C:17](=[O:19])[CH3:18])[CH2:21][CH2:22][C:23]=3[CH:30]=2)=[O:16])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCCCC(=O)O)CC1
Reactant: CC(=O)N1CCc2ccccc2CC1
Product: CC(=O)N1CCc2ccc(C(=O)CCCCC3CCN(C(C)=O)CC3)cc2CC1

Procedure:
Using 5-(1-acetyl-4-piperidinyl)valeric acid and 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine, the procedure of Example 23-1 was otherewise repeated to provide the title compound as colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[C:11]([CH3:13])[S:12][C:5]=2[CH2:4]1)[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[S:12][C:11]([CH3:13])=[CH:10][C:6]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CCN1Cc2sc(C)cc2C(O)C1
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: CCN1Cc2sc(C)cc2C(Oc2ccc(Cl)c(Cl)c2)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 10) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1.Cl.O1CCOC[CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:27])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-c2ccc3c(c2)NC(=O)C32CCCC2)c1
Yield: 91.4 %

Procedure:
A suspension of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzoic acid (preparation 38, 0.47 g, 1.5 mmol) and a 4M solution of hydrochloric acid in dioxane (2.00 mL, 8.0 mmol) in methanol (2 mL) was heated in a sealed tube at 80° C. with stirring. After stirring overnight the mixture was cooled and ethyl acetate and saturated aqueous potassium carbonate solution were added. The organic layer was washed with brine, dried (MgSO4) and evaporated in vacuo. The resultant oil was taken up in a small amount of ethyl acetate and the suspension was filtered. The filtrate was evaporated to give the title compound (0.46 g, 86%) as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]=2[C:22]([O:24]C)=[O:23])[N:4]=1.[OH-].[K+]>CO.COCC>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]=2[C:22]([OH:24])=[O:23])[N:6]=1
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2ncccc12
Agent: CCOC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)nc(Oc2ccc3ncccc3c2C(=O)O)n1
Yield: 65.2 %

Procedure:
0.8 g of methyl 6-[(4,6-dimethoxypyrimidin-2-yl)oxy]quinolin-5-carboxylate was dissolved in 10 ml of methanol and 20 ml of methoxyethane, and 5 ml of an aqueous solution containing 0.39 g of potassium hydroxide was added thereto at 40° C. The mixture was extracted with dichloromethane. The aqueous layer was acidified (pH=4) with a 10% hydrochloric acid aqueous solution, and formed precipitates were collected by filtration and dried to obtain 0.5 g (yield: 66.0%) of the desired compound. mp: 195°-198° C.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@@H:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:13][CH2:12][O:11]1)C1C=CC=CC=1>CO.C(O)C.[Pd]>[CH2:17]([O:16][C@H:15]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:9][OH:8])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCO[C@H]1CCCO[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCCCCCCCCCCCCCCCO[C@H]1CCCO[C@H]1CO

Procedure:
1.409 g of dl-cis-2-benzyloxymethyl-3-hexadecyloxytetrahydropyran (prepared as described in Preparation 10) was dissolved in 100 ml of a 1:1 by volume mixture of methanol and ethanol. 0.70 g of a 10% w/w palladium-on-activated carbon catalyst was then added to the resulting solution. Catalytic reduction using the same procedure as described in Preparation 8 yielded 1.116 g of a crude substance, which was then subjected to column chromatography through 30 g of silica gel. The fraction eluted with mixtures of diethyl ether and hexane ranging from 1:20 to 1:5 by volume gave 1.031 g of the title compound, melting at 42°-43° C. (cold hexane).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22]>CN(C=O)C.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:22]#[C:21][C:20]([CH3:24])([CH3:23])[CH3:19])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: C#CC(C)(C)C
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CC(C)(C)C)s1
Yield: 238.4 %

Procedure:
A mixture of 5-bromo-thiophene-2-carboxylic acid ethyl ester (7 g, 30 mmol), copper iodide (1.2 g, 6 mmol), triethylamine (20 mL) in DMF (100 mL) was degassed in a 350 mL pressure bottle. Then tris(dibenzylideneacetone)dipalladium(0) (2.1 g, 3 mmol) and 3,3-dimethyl-but-1-yne (18.3 mL, 150 mmol) were added and heated at 80 degree for 3 hours. The reaction mixture was filtered on celite and washed with ethyl acetate. The solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with water. After drying and concentration, the crude residue was purified by flash chromatography to yield 16.9 g (95%) of 5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid ethyl ester as a yellow oil.